After a decline in rates of infection over several decades, a disturbing increase in the incidence of tuberculosis (TB) is occurring. Because TB is highly contagious it poses a profound threat to public health. TB bacteria are easily passed from person to person in airborne droplets formed when a person with active TB sneezes or coughs.
Even more alarming has been the rise of multidrug-resistant tuberculosis (MDRTB). Prior to 1984, about 10 percent of TB bacteria isolated from patients in the United States were resistant to even a single antibacterial drug. In 1984, 52 percent of patients were infected with Mycobacterium tuberculosis (also referred to as tubercle bacilli) resistant to at least one drug, and 32 percent were resistant to one or more drugs. Outbreaks of MDRTB have been reported in 13 states. Ten percent of the recorded MDRTB cases to date have occurred in previously healthy people whose mortality rate--70 to 90 percent--has been nearly the same as that of immunosuppressed persons with MDRTB (Snider and Roper, 1992).
The United States Centers for Disease Control (CDC) has released preliminary results of a joint study with the New York State Health Department showing that cases of drug-resistant TB have more than doubled since 1984. CDC data from the first quarter of 1991 show that many of these drug-resistant strains are resistant to both of the frontline TB drugs, rifampin and isoniazid. Outbreaks of MDRTB have occurred in hospitals in Miami and New York City, as well as in the New York State prison system. In one hospital in New York City, the median interval between diagnosis of MDRTB and death was only four weeks. Additional clusters of MDRTB were reported to the CDC in 1990 and 1991 from Mississippi, Missouri, and Michigan.
There are five frontline drugs known to be highly effective against Mycobacterium tuberculosis and five second-line drugs that can be used when resistance to one or more of the frontline drugs is detected. Ironically, in the United States, until April 1992, there were shortages of antituberculosis drugs, some of which are crucially needed when resistance to the frontline drugs rifampin and isoniazid is present. These shortages had occurred because several pharmaceutical companies had ceased production of these drugs.
Because of its persistence in the body, the tubercle bacillus is a notoriously difficult pathogen to control. Although bacille Calmette-Guerin (BCG) vaccine protects against severe tuberculosis meningitis and disseminated TB in children, its efficacy against pulmonary TB in adults has varied widely in different parts of the world. Treatment of conventional TB is effective, but expensive, requiring daily treatment with multiple drugs for a minimum of six months. There is a common tendency among TB patients to stop taking their drugs when the drugs begin to have their beneficial effect or to take the medications only intermittently. When this happens, relapses are frequent and very often are caused by drug-resistant tubercle bacilli that have survived the initial course of treatment. The emergence of drug-resistant M. tuberculosis is in many ways an index of individual compliance with antituberculosis chemotherapy and of the inability of the health care infrastructure to ensure adequate treatment. Many public health agencies that once could play key roles in this process have had their budgets cut drastically in recent years and hence are unable to perform this crucial service.
MDRTB is extraordinarily difficult to treat, and a majority of patients do not respond to therapy. Total treatment costs for an individual with MDRTB can be as much as ten times the cost of traditional treatment; the cost of the treatment drugs alone can be as much as 21 times as great.
The preferred treatment for classical TB consists of isoniazid, rifampin, and pyrazinamide. For patients whose tubercle bacilli are thought to be resistant to isoniazid, a fourth drug, ethambutol, is commonly added to the regimen until drug susceptibility results are known. Isolates of tubercle bacilli resistant to both isoniazid and rifampin, now representing about 20 percent in some cities, require specialized treatment with additional medications, which may include streptomycin and ciprofloxacin for almost two years.
The tubercle bacillus is a slow-growing organism. Three to six weeks are needed to grow the bacteria in the clinical laboratory, and an additional three to six weeks are needed to screen for antibiotic resistance. Such extended laboratory procedures can result in a delay in diagnosis, which means that patients with unrecognized drug-resistant TB may be treated ineffectively and remain infectious for a longer period. In HIV-positive individuals, MDRTB usually causes death within 4 to 16 weeks after being diagnosed, which is often before laboratory tests on drug susceptibility and resistance can be completed.
There is no evidence that mutation rates in M. tuberculosis organisms have increased or that increased virulence is to blame for the recent deadly outbreaks of TB. It is likely that drug-resistant forms of tuberculosis arose because of patient noncompliance with the 6- to 12-month regimen of antibiotics required to treat TB. Ineffective treatment regimens also play a role in the rising incidence of TB. To address noncompliance, some states with high TB rates are considering approaches to outreach, such as expanding directly observed therapy (DOT); others may reestablish inpatient facilities similar to the TB sanatoria of the first half of this century. Standard treatment regimens for TB have also been updated. Instead of taking two or three antibiotics, TB patients now take four. Still, as noted earlier, the current shortages of antituberculosis drugs in the United States have made even standard treatment difficult.
Tryptanthrin (indolo-[2,1-b]quinazolin-6,12-dione) is a material that is produced naturally in some plant species, and has been produced synthetically by a base catalyzed condensation of isatin and isatoic anhydride (L. A. Mitscher et al., "Antimicrobial Agents From Higher Plants. New Synthesis and Bioactivity of Tryptanthrin (Indolo-[2,1-b]-quinazolin-6,12-dione) and its Analogs," Heterocycles 15(2):1017-1021 (1981)). Tryptanthrin and some of its analogs have been shown to exhibit some antimicrobial activity against various bacterial and yeast species, including Staphylococcus aureus, Klebsiella pneumoniae, nonpathogenic Mycobacterium smegmatis and Candida albicans, although activity has been found to be highly variable depending on individual species and substitution of the parent compound (see Mitscher et al., supra). To date, however, there has been no indication in the prior art that tryptanthrin exhibits antimicrobial activity against pathogenic mycobacteria, that various derivatives of this compound may exhibit enhanced activity, or that various derivatives may be highly useful in the treatment of MDRTB.